The overall goal of the Lymphoma SPORE at Baylor College of Medicine and The Methodist Hospital is to devise in the laboratory, and validate in the clinic, interventional strategies, with the broad objective of improving outcome in Hodgkin's and non-Hodgkin's lymphomas and in chronic lymphocytic leukemia (CLL). The underlying theme of our program is that increased understanding of the fundamental biology of lymphoma cells is needed to drive the development of novel therapies for this group of malignancies. A multidisciplinary team of laboratory and clinical investigators at Baylor and The Methodist Hospital will pursue this goal through judicious integration of their current research interests. In Project 1, Drs. Rooney and Bollard will validate new target antigens in Hodgkin's lymphoma, particularly cancer testis antigens, before testing cytotoxic T lymphocytes (CTLs) specific for these targets in patients with relapsed disease. Drs. Dotti and Brenner in Project 2 plan to test T cells engineered to express anti-K-light-chain antibody, as a chimeric receptor, in patients with follicular lymphomas expressing K-positive immunoglobulins, with the aim of improving tumor cell recognition by the CTLs. They also propose to combine two B-cell-targeting moieties with distinct modes of cytotoxicity on the same CTL to enhance tumor cell killing by the modified T cells. The principal aim of Project 3, led by Drs. Gottschalk and Heslop, is to improve outcome in EBV-positive Hodgkin's and non-Hodgkin's lymphomas by broadening the tumor specificity of CTLs and increasing their expansion in patients by providing additional antigen by vaccination. Project 4 will exploit an emerging concept in tumor immunology - that the negative effects of T-regulatory (Treg) cells in the tumor microenvironment can blunt the antitumor activity of CTLs or other immunotherapies. Thus, Drs Wang and Mims will evaluate whether the activation of Toll-like receptors on Treg cells, using specific ligands, can lessen or reverse the suppressive function of these cells, thus releasing the potential of T-cell-mediated immunity against the tumor. Finally, in Project 5, Drs. Brenner and Goodell, building on observations in a CLL vaccine study, will test the hypothesis that CLL may harbor, cancer stem cells whose defining molecules could be targeted for more productive therapeutic interventions. Each of these projects is clearly translational, addressing issues that arose in a bidirectional pathway, initially either from observations in the clinic (Projects 3 and 5) or from laboratory findings (Projects 1, 2 and 4). Five cores are planned to meet the specialized requirements of this SPORE: Administration, Clinical Research, Biostatistics and Data Management, Cell and Vector Production, and Tissue Bank. The Lymphoma SPORE will also support a Developmental Research Program and a Career Development Program to foster the advancement of pilot translational projects and of young investigators whose research interests focus on lymphoma. [unreadable] [unreadable] [unreadable] [unreadable]